Pyrazole derivatives and diabetic medicine containing them

ABSTRACT

The present invention provides pyrazole-O-glycoside derivatives represented by the following formulae, used as a diabetic medicine.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/427,959, filed on May 2, 2003 now U.S. Pat. No. 6,815,428, which is acontinuation of International Patent Application No. PCT/JP01/09555,filed on Oct. 31, 2001, and claims priority to Japanese PatentApplication No. 2000-335851, filed on Nov. 2, 2000, and Japanese PatentApplication No. 2001-13 1264, filed on Apr. 27, 2001, all of which areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates to new pyrazole derivatives and diabeticmedicine which have those compounds as an active ingredient.

Na⁺-dependent glucose transporter (SGLT) is a membrane protein whichtransports glucose, and SGLT-1 and SGLT-2 are known. SGLT-2 mainlyexpresses in renal uriniferous tubules. Glucose that is filtered inglomeruli is reabsorbed at the renal uriferous tubules via SGLT, and theglucose taken is reused in the body through the bloodstream. When SGLTis inhibited, the amount of the glucose reabsorbed at renal uriniferoustubules lowers, and the glucose is discharged through urine. As aresult, it is considered that the level of blood sugar decreases. At thepresent time, no medicine is clinically used such as that inhibitingreabsorption of glucose in the kidney.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide new pyrazolederivatives.

The object of the present invention is also to provide a pharmaceuticalcomposition containing the new compounds.

The object of the present invention is also to provide a pharmaceuticalcomposition for the treatment of diabetes which comprises the newcompound.

The object of the present invention is to find and providediabetic-medicine which is easy to synthesize, less toxic and has highercurative effect.

The present invention also intends to provide urinary sugar excretioninducers which have the new compounds.

Further, the present invention intends to provide the use of the newcompounds for producing a pharmaceutical composition which reduces renalglucose reabsorption at renal uriniferous tubules.

The inventors have synthesized various derivatives (1A) or (1B) whereinglucose (namely, β-D-glucopyranose) or glucuronic acid (namely,β-D-glucopyranoside uronic acid) is bonded to pyrazole, and vigorouslyinvestigated the action of those derivatives on urinary sugar excretion.As the result of animal tests, they have found that the compounds ofgeneral formula (1A) or (1B) have the outstanding action on urinarysugar excretion and completed the present invention. These compoundshave not ever been synthesized and, therefore, are completely newpyrazole-O-glycoside derivatives and pyrazole-O-glucuronide derivatives.

Namely, the present invention provides pyrazole derivatives of thefollowing general formula (1A) or (1B) or pharmaceutically acceptablesalts thereof:

wherein X represents a β-D-glucopyranosyl group, of which one or morehydroxyl groups may be acylated or β-D-glucuronyl group, of which one ormore hydroxyl groups may be acylated and carboxyl group may beesterified; Y represents a lower alkyl group or perfluoro lower alkylgroup; Z represents a hydrogen atom, lower alkyl group, perfluoro loweralkyl group, aralkyl group or phenyl group; R1 to R5 may be the same ordifferent and represent a hydrogen atom, lower alkyl group, perfluorolower alkyl group, lower alkoxy group, perfluoro lower alkoxy group,lower alkylthio group, perfluoro lower alkylthio group, lower alkylamino group, halogeno group, lower alkanoyl group, lower alkenyl groupor lower alkynyl group, and n represents an integer from 0 to 3.

The present invention provides a pharmaceutical composition whichcomprises the above-mentioned pyrazole derivatives or pharmaceuticallyacceptable salts thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for thetreatment of diabetes which comprises the above-mentioned pyrazolederivatives or pharmaceutically acceptable salts thereof as an activeingredient.

The present invention also provides urinary sugar excretion inducerswhich comprise the above-mentioned pyrazole derivatives orpharmaceutically acceptable salts thereof as an active ingredient.

Further, the present invention provides the use of the above-mentionedpyrazole derivatives or pharmaceutically acceptable salts thereof forproducing a pharmaceutical composition which reduces renal glucosereabsorption at renal uriniferons tobules.

BEST MODE FOR CARRYING OUT THE INVENTION

The term “lower” in the present specification indicates 1 to 6 carbonatoms, preferably 1 to 4 carbon atoms. The terms “alkyl”, “alkenyl” and“alkynyl” in alkyl group, perfluoro lower alkyl group, lower alkoxygroup, perfluoro lower alkoxy group, lower alkylthio group, perfluorolower alkylthio group, lower alkyl amino group, lower alkanoyl group,lower alkenyl group or lower alkynyl group may be linear or branched.

An alkyl part in “aralkyl group” in the present specification is a loweralkyl group. An aryl part in “aralkyl group” is a monocyclic or bicyclicaromatic substituent having 5 to 12 carbon atoms.

Examples of the alkyl group include methyl group, ethyl group, propylgroup, butyl group, pentyl group, isopropyl group, isobutyl group andisopentyl group. The perfluoro lower alkyl group is, for example, atrifluoromethyl group. Examples of the lower alkoxy group are methoxygroup, ethoxy group, propyloxy group and isopropyloxy group. Theperfluoro lower alkoxy group is, for example, a trifluoromethoxy group.The lower alkylthio group includes such as methylthio group, ethylthiogroup and propylthio group. The perfluoro lower alkylthio group is, forexample, trifluoromethylthio group. The lower alkyl amino group includessuch as methyl amino group, ethyl amino group, propyl amino group,dimethyl amino group and diethyl amino group. The lower alkanoyl groupis, for example, acetyl group and propionyl group. The lower alkenylgroup includes such as vinyl group, propenyl group and2-methyl-1-propenyl group. The lower alkynyl group is, for example,ethynyl group and propynyl group. The aralkyl group includes such asbenzyl group, benzyl group of which a benzene ring may have one or moresubstituents, phenethyl group and phenethyl group of which a benzenering may have one or more substituents. The substituents of benzyl groupand phenethyl group herein include lower alkoxy group, lower alkylgroup, halogeno group and halogeno lower alkyl group. Examples of thehalogeno group are fluorine atom, bromine atom, chlorine atom and iodineatom.

The groups for acylating hydroxyl group include acyl group and carbamategroup; acyl group includes such as acetyl group, propionyl group,benzoyl group and pivaloyl group; carbamate group includes such asmethyl carbonate group, ethyl carbonate group, propyl carbonate group,isopropyl carbonate group and phenyl carbonate group. The groups foresterifying carboxyl group include lower alkyl group such as methylgroup, ethyl group, propyl group and isopropyl group.

In the above-mentioned general formula (1A) or (1B), one or morehydroxyl groups of β-D-glucopyranosyl group which is a group representedby X may be acylated. Especially, one or more hydroxyl groups of thesaid group may be acylated with the groups selected from alkanoyl groupshaving 2 to 20 carbon atoms, lower alkoxycarbonyl groups and benzoylgroup. Examples of such groups are 6-O-acetyl-β-D-glucopyranosyl groupand 6-O-methoxycarbonyl-β-D-glucopyranosyl group.

Further, one or more hydroxyl groups of β-D-glucuronyl group which is agroup represented by X may be acylated and its carboxyl group may beesterified. Especially, one or more hydroxyl groups of the said groupmay be acylated with the groups selected from alkanoyl groups having 2to 20 carbon atoms, lower alkoxycarbonyl groups and benzoyl group andits carboxylic acid may be esterified with lower alkyl group. An exampleof such groups is 6-O-methyl-β-D-glucuronyl group.

The groups represented by X are preferably β-D-glucopyranosyl group,6-O-acetyl-β-D-glucopyranosyl group,6-O-methoxycarbonyl-β-D-glucopyranosyl group, β-D-glucuronyl group and6-O-methyl-β-D-glucuronyl group. Among them, β-D-glucopyranosyl groupand β-D-glucuronyl group are more preferable. Particularly, the grouprepresented by X is preferably β-D-glucopyranosyl group of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl groups having 2 to 20 carbon atoms, lower alkoxycarbonyl groupsand benzoyl group. It is more preferable that the group is acylated withalkanoyl group having 2 to 6 carbon atoms or lower alkoxycarbonyl group.Among them, one hydroxyl group is preferably acylated. Most preferably,the hydroxyl group connected to a carbon atom at the 6th position isacylated. Examples of such groups represented by X are6-O-acetyl-β-D-glucopyranosyl group and6-O-methoxycarbonyl-β-D-glucopyranosyl group.

The groups represented by Y are preferably lower alkyl group having 1 to3 carbon atoms or perfluoro lower alkyl group having 1 to 6 carbonatoms. A methyl group and trifluoromethyl group are particularlypreferable.

The groups represented by Z are preferably hydrogen atom and lower alkylgroup having 1 to 6 carbon atoms. A hydrogen atom, lower alkyl grouphaving 1 to 3 carbon atoms, unsubstituted aralkyl group or aralkyl groupof which an aryl part at the 4th position is substituted andunsubstituted phenyl group are also preferable. Further, hydrogen atom,methyl group, ethyl group, propyl group, isopropyl group, unsubstitutedbenzyl group or benzyl group of which an aryl part at the 4th positionis substituted and unsubstituted phenyl group are more preferable. Amongthem, hydrogen atom, methyl group, ethyl group, propyl group andisopropyl group are more preferable, and isopropyl group is particularlypreferable.

The groups represented by R1 to R5 are preferably lower alkyl grouphaving 1 to 6 carbon atoms, lower alkylthio group having 1 to 6 carbonatoms, halogeno atom, lower alkoxy group, lower alkenyl group and loweralkynyl group. A methyl group, ethyl group, methylthio group, ethylthiogroup, fluorine atom, methoxy group, vinyl group, propenyl group,ethynyl group and propynyl group are more preferable. It is particularlypreferable that one or two groups represented by R1 to R5 are one of theabove-mentioned preferable groups and the rest of the groups arehydrogen atom. In this case, at least R3 is preferably one of theabove-mentioned preferable groups. When two groups in R1 to R5 are oneof the above-mentioned preferable groups, they may be the same ordifferent from each other, but they are preferably different from eachother. Further, when R3 is either lower alkyl group, lower alkoxy group,lower alkenyl group or lower alkynyl group, R4 or R5 is preferably afluorine atom. It is preferable that one of R1, R2, R4 and R5 ishalogeno group, or R1, R2, R4 and R5 are all hydrogen atom and R3 islower alkyl group, lower alkoxy group, lower alkenyl group or loweralkynyl group. It is also preferable that one of R1, R2, R4 and R5 is afluorine atom and R3 is methyl group, ethyl group, methoxy group, vinylgroup or ethynyl group.

It is preferable that n represents an integer 1.

Y in general formula (1A) or (1B) is preferably trifluoromethyl group.

Further, it is preferable that in general formula (1A) or (1B), Y istrifluoromethyl group and n is 1.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucopyranosyl group, ofwhich one or more hydroxyl groups may be acylated with the groupsselected from alkanoyl group having 2 to 20 carbon atoms, loweralkoxycarbonyl group and benzoyl group.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucuronyl group, of whichone or more hydroxyl groups may be acylated with the groups selectedfrom alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonylgroup and benzoyl group and its carboxylic acid may be esterified withalkyl group.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucopyranosyl group.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is 6-acetyl-β-D-glucopyranosylgroup.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is 6-carbomethoxy-β-D-glucopyranosylgroup.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucuronyl group.

It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is 6-methyl-β-D-glucuronyl group.

It is also preferable that in general formula (1A) or (1B), X isβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with the groups selected from alkanoyl group having 2 to 20carbon atoms, lower alkoxycarbonyl group and benzoyl group.

It is also preferable that in general formula (1A) or (1B), X isβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with lower alkoxycarbonyl group.

It is also preferable that in general formula (1A) or (1B), Y is loweralkyl group having 1 to 3 carbon atoms or perfluoro lower alkyl grouphaving 1 to 6 carbon atoms; n is 1; X is β-D-glucopyranosyl group, ofwhich one or more hydroxyl groups may be acylated with the groupsselected from alkanoyl group having 2 to 20 carbon atoms, loweralkoxycarbonyl group and benzoyl group; Z is a hydrogen atom, loweralkyl group having 1 to 3 carbon atoms, unsubstituted aralkyl group oraralkyl group of which an aryl part at the 4th position is substitutedor unsubstituted phenyl group; one of R1, R2, R4 and R5 is a halogenogroup, or R1, R2, R4 and R5 are all hydrogen atom and R3 is a loweralkyl group, lower alkoxy group, halogeno group, lower alkenyl group orlower alkynyl group.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkyl groupand R4 or R5 is a fluorine atom.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group; n is 1; X is β-D-glucopyraniosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkoxy groupand R4 or R5 is a fluorine atom.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkynyl group.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is lower alkynyl groupand R4 or R5 is a fluorine atom.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkenyl group.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkenyl groupand R4 or R5 is a fluorine atom.

It is also preferable that in general formula (1A) or (1B), Y is amethyl group or trifloromethyl group; n is 1; X is β-D-glucopyranosylgroup, of which one or more hydroxyl groups may be acylated with thegroups selected from alkanoyl group having 2 to 20 carbon atoms, loweralkoxycarbonyl group and benzoyl group; Z is a hydrogen atom, isopropylgroup, aralkyl group or phenyl group; one of R1, R2, R4 and R5 is afluorine atom and R3 is a methyl group, ethyl group, methoxy group,vinyl group or ethynyl group.

The compounds or pharmaceutically acceptable salts thereof describedbelow are also preferable:

-   4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-ethylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-propylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-isopropylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-methylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-propylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-isopropylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-vinylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-((4′-methylthiophenyl)methyl)-5′-trifluoromethyl-3′-O-(6-0-carbomethoxy-β-D-glucopyranosyl)-1H-pyrazole;-   4′-((4′-ethylphenyl)methyl)-5′-(trifluoromethyl)-3′-O-(6-0-carbomethoxy-β-D-glucopyranosyl)-1H-pyrazole;-   4′-((4′-methylthiophenyl)methyl)-5′-trifluoromethyl-3′-O-(2,3,4,6-0-tetraacetyl-β-D-glucopyranosyl)-1H-pyrazole;-   4′-((4′-ethylphenyl)methyl)-5′-(trifluoromethyl)-3′-O-(2,3,4,6-0-tetraacetyl-β-D-glucopyranosyl)-1H-pyrazole;-   4-[(4-trifluoromethoxyphenyl)methyl]-5-trifluoromethyl-1H    -pyrazole-3-O-β-D-glucopyranioside;-   4′-[(4′-trifluoromethoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-0-tetraacetyl)-β-D-glucopyranoside;-   4′-[(4′-trifluoromethoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((3-fluoro-4-methoxyphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((3-fluoro-4-methylphenyl)methyl-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((2-fluoro-4-methoxyphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((2-fluoro-4-methylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((2-fluoro-4-ethylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((3-fluoro-4-ethylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((4-ethynylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((2-fluoro-4-ethynylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((3-fluoro-4-ethynylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((4-(1-propynyl)phenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((3-fluoro-4-(1-propynyl)phenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4′-((2-fluoro-4-(1-propynyl)phenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-((3-fluoro-4-methoxyphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-fluoro-4-methylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((2-fluoro-4-methoxyphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((2-fluoro-4-methylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((2-fluoro-4-ethylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-fluoro-4-ethylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-ethynylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((2-fluoro-4-ethynylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-fluoro-4-ethynylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-(1-propynyl)phenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((3-fluoro-4-(1-propynyl)phenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((2-fluoro-4-(1-propynyl)phenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-ethylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-propylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-isopropylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranioside    uronic acid;-   4-((4-methylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-propylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-isopropylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-vinylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-ethynylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((4-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((3-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((3-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((3-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-((3-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D    -glucopyranoside uronic acid;-   methyl    4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranouronate;    and-   ethyl    4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranouronate.

Among the above-mentioned examples, the following compounds orpharmaceutically acceptable salts thereof are particularly preferable:

-   4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;-   4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside    uronic acid;-   4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(4-ethylphenyl)methyl]-1′-[(4′-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;-   4′-[(2-fluoro-4-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;-   4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;    and-   4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole3′-O-(6-carbomethoxy)-β-D-glucopyranoside.

Among the above-mentioned examples, the following compounds orpharmaceutically acceptable salts thereof are particularly preferable:

The following compounds or pharmaceutically acceptable salts thereof arealso preferable:

-   4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl    -1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside; and-   4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside.

As methods for producing pyrazole derivatives (1A) or (1B) in thepresent invention, for example, the compounds are produced in accordancewith methods described below when X is β-D-glucopyranosyl group orβ-D-glucuronyl group.

For example, the compound shown as the compound (2) of the presentinvention can be obtained by methods described as follows.1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-(trifluoromethyl)-3H-pyrazole-3-one(4) (prepared by methods described in J. Med. Chem. 1996, 39, 3920–3928)is reacted with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in thepresence of potassium carbonate in chloroform-water overnight. Theproduct is purified by using such as the chromatography andtetra-O-acetyl intermediate (6) can be obtained, and then thisintermediate is deprotected in a potassium hydroxide aqueous solution toobtain the intended compound (2).

For example, the compound shown as the compound (3) of the presentinvention can be obtained by methods described as follows.1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-(trifluoromethyl)-3H-pyrazole-3-one(7) (prepared by methods described in J. Med. Chem. 1996, 39, 3920–3928)and 2,3,4-tri-O-benzylβ-D-glucopyranoside uronic acid benzyl ester (8)are reacted with triphenylphosphane and diethyl azodicarboxylate (DEAD)in tetrahydrofuran for 1.5 hours. The product is purified by using suchas the chromatography and tetra-benzyl intermediate (9) can be obtained.Then this intermediate is deprotected under hydrogen atmosphere by 20%Pd(OH)₂ to obtain the intended compound (3).

For example, the compound shown as the compound (15) of the presentinvention can be obtained by methods described as follows. A hydroxylgroup of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-(trifluoromethyl)-3H-pyrazole-3-one(7) is protected by tert-butyldimethylsilylchloride to obtain compound(10). Benzyl alcohol is reacted with a nitrogen atom on pyrazole of thecompound in accordance with Mitsunobu reaction to obtain (11). TBS groupis then deprotected by diluted hydrochloric acid and reacted with2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (5) in the presence ofpotassium carbonate in chloroform-water overnight. The product ispurified by using such as the chromatography and tetra-O-acetylintermediate (13) can be obtained. Then this intermediate is deprotectedin a potassium hydroxide aqueous solution to obtain (14). A primaryhydroxyl group of the obtained compound (14) is reacted with methylchlorocarbonate to obtain the intended compound (15).

For example, the compound shown as the compound (21) of the presentinvention can be obtained by methods described as follows. Ethylacetoacetate and 3-fluoro-4-methoxybenzaldehyde are reacted withtrimethylsilylchloride and sodium iodide in acetonitrile to obtain anintermediate (16) and by forming a ring structure with hydrazine,1,2-dihydro-4-[(3-fluoro-4-methoxylphenyl)methyl]-5-methyl-3H-pyrazole-3-one(17) can be obtained. Then, 2,3,4,6-tetrabenzylglucopyranose is reactedwith a hydroxyl group on pyrazole thereof in accordance with Mitsunobureaction to obtain (18) and a nitrogen atom in the 1st position ofpyrazole thereof is isopropylated by cesium carbonate and isopropyliodide to obtain compound (19). A benzyl-protecting group of (19) isdeprotected under hydrogen atmosphere by 20% Pd(OH)₂ to obtain compound(20), and a hydroxyl group at the 6th position of (20) is reacted withmethyl chlorocarbonate in collidine to obtain the intended compound(21).

For example, the compound shown as the compound (27) of the presentinvention can be obtained by methods described as follows. Ethylacetoacetate and 3-fluoro-4-methlylbenzaldehyde are reacted withtrimethylsilylchloride and sodium iodide in acetonitrile to obtain anintermediate (22) and by forming a ring structure with hydrazine,1,2-dihydro-4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3H-pyrazole-3-one(23) can be obtained. Then, 2,3,4,6-O-tetraacetyl-α-D-glucopyranosylbromide is reacted with hydroxyl group on pyrazole thereof by silvercarbonate to obtain (24) and a nitrogen atom at the 1st position ofpyrazole thereof is isopropylated by cesium carbonate and isopropyliodide to obtain compound (25). An acetyl-protecting group of compound(25) is deprotected by 1N LiOH to obtain compound (26), and a hydroxylgroup at the 6th position of compound (26) is reacted with methylchlorocarbonate in collidine to obtain the intended compound (27).

Pyrazole-O-glycoside derivatives and pyrazole-O-glucuronide derivativesof the present invention produced by the above-mentioned methods can beeasily isolated and purified from the reaction mixture by ordinarymethods for isolation and purification, such as the extraction bysolvents, chromatography and crystallization.

A hydroxyl group of the compounds of the present invention may besubstituted with appropriate substituents which are exchanged to ahydroxy group in vivo. The substituents of hydroxyl group are, forexample, acyl group and carbamate group. An acyl group includes such asalkanoyl group having 2 to 20 carbon atoms and benzoyl group andcarbamate group includes such as lower alkoxycarbonyl group. Especially,the substituents of hydroxyl group of glucopyranosyl group arepreferably carbamate group which is lower alkoxycarbonyl group and morepreferably methoxycarbonyl group. A carboxyl group of the compounds ofthe present invention may be substituted with appropriate substituentswhich are exchanged to a carboxyl group in vivo. The substituents ofcarboxyl group are, for example, lower alkyl group such as methyl groupand ethyl group.

When the compounds shown in general formula (1A) or (1B) of the presentinvention can form salts thereof, the salts should be pharmaceuticallyacceptable. When an acidic group exists in the formula, the salts to theacidic group include such as ammonium salt; salts of alkali metal likesodium and potassium; salts of alkali earth metal like calcium andmagnesium; aluminum salt; zinc salt; salts of organic amine liketriethylamine, ethanolamine, morpholine, piperidine anddicyclohexylamine and salts of basic amino acid like arginine andlysine. When a basic group exists in the formula, the salts to the basicgroup include such as salts of inorganic acid like hydrochloric acid,sulfuric acid and phosphoric acid; salts of organic carboxylic acid likeoxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleicacid, fumaric acid, tartaric acid, succinate and glutamic acid and saltsof organic sulfonic acid like methaniesulfonic acid andp-toluenesulfonic acid. The salts can be formed by combining thecompounds of general formula (1A) or (1B) and necessary acid or base inthe appropriate amount and ratio in a solvent and decomposer. They canbe also obtained by the cation or anion exchange from the form of othersalts.

The compounds of general formula (1A) or (1B) of the present inventioninclude solvates such as hydrates and alcohol adducts.

In the present invention, an inhibitor having the compounds of generalformula (1A) or (1B) or salts thereof as an active ingredient can beused as pharmaceutical compositions, in particular, for the treatment ofdiabetes.

In the present invention, when the pyrazole-O-glycoside derivatives andpyrazole-O-glucuronide derivatives are used as the pharmaceuticalcompositions, for example, diabetic medicine, they can be given by oralor parenteral administration such as intramuscular, hypodermic andintravenous administrations and suppository. Though the dosage given forthe above-mentioned purpose is determined depending on the therapeuticeffect, administration method, treatment period, age and weight of thepatient, the daily dose for adults is usually 1 μg to 10 g by oraladministration and 0.01 μg to 1 g by parenteral administration.

Further, when pyrazole-O-glycoside derivatives andpyrazole-O-glucuronide derivatives of the present invention are preparedas an oral preparation, they can be prepared by ordinary methods afteradding diluent bases and, if necessary, binders, disintegrants,lubricants, coloring agents and flavoring agents, in the form oftablets, powders, pills, granules, capsules, suppositories, solutions,dragees, depots or syrups. Diluent bases include such as lactose,cornstarch, sucrose, glucose, sorbit and crystalline cellulose, Bindersinclude such as polyvinyl alcohol, polyvinyl ether, ethyl cellulose,methyl cellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropyl cellulose, hydroxypropyl starch and polyvinylpyrrolidone;Disintegrants include such as starch, gelatin powder, crystallinecellulose, calcium carbonate, sodium hydrogen carbonate, calciumcitrate, dextran and pectin; Lubricants include such as magnesiumstearate, talc, polyethylene glycols, silica and hardened vegetable oil;Coloring agents include those whose addition to pharmaceutical compoundsis permitted; Flavoring agents includes such as cocoa powder, menthol,aromatic acid, mentha oil, borneol and cassia powder. Their tablets andgranules may be coated with sugar, gelatin and other coating agents, ifnecessary.

When injectable solutions are prepared, they can be prepared by ordinarymethods after adding pH adjuster, buffering agents, stabilizing agentsand preserving agents, if necessary, in the form of hypodermic,intramuscular, and intravenous injectable solutions.

EXAMPLES

The following Examples will further illustrate the present invention.They are preferred embodiments of the present invention, which by nomeans limit the invention.

Example 1

Synthesis of4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside

Process 1

Synthesis of4′-((4′-methylthiophenyl)methyl)-5′-(trifluoromethyl)-1H-pyrazole-3′-O-(2,3,4,6-O-tetracetyl)-β-D-glucopyranoside

519 mg (1.80 mmol) of1,2-dihidro-4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-3H-pyrazole-3-one(prepared by methods described in J. Med. Chem. 1996, 39, 3920–3928),1.258 g (3.06 mmol) of ², 3,4,6-O-tetraacetyl-α-D-glucopyranosylbromide, 112 mg (0.36 mmol) of benzyl tri-n-butylammonium chloride and1.244 g (9.0 mmol) of potassium carbonate were stirred at roomtemperature for 21 hours after adding 0.1 mL of water and 4 mL ofchloroform. After the reaction was completed, the mixture was controlledby 10% hydrochloric acid to show pH7. After adding 5 mL of chloroformand removing water layer, organic layer was washed with 4 mL ofsaturated sodium bicarbonate aqueous solution and 4 mL of saturatedaqueous sodium chloride solution, respectively. After the product wasdried with magnesium sulfate and concentrated, it was purified by silicagel column chromatography (chloroform:methanol=20:1 (V/V)) to obtain 870mg (1.41 mmol) of4′-((4′-methylthiophenyl)methyl)-5′-(trifluoromethyl)-1H-pyrazole-3′-O-(2,3,4,6-O-tetraacetyl)-β-D-glucopyranosidein the form of pale yellow oily product.

¹H-NMR (300 MHz, DMSO-d6) δ: 1.92(3H, s), 2.03(3H, s), 2.05(3H, s),2.10(3H, s), 2.45(3H, s), 3.74(2H, s), 4.21(1H, dd, J=2.4, 12.6 Hz),4.28(1H, dd, J=4.2, 12.6 Hz), 5.19–5.28(4H, m), 5.41(1H, d, J=6.3 Hz),7.09(2H, d, J=8.1 Hz), 7.16(2H, d, J=8.1 Hz). ESI-MS(m/z): 619[(M+H)⁺],617[(M−H)⁻]

Process 2

Synthesis of4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside

804 mg (1.30 mmol) of4′-((4′-methylthiophenyl)methyl)-5′-(trifluoromethyl)-1H-pyrazole-3′-O-(2,3,4,6-O-tetraacetyl)-β-D-glucopyranosidein the form of pale yellow oil was dissolved in 6 mL of ethanol. 0.8 mLof 50% aqueous solution of potassium hydroxide was added thereto and themixture was stirred at room temperature for 10 minutes. After thereaction was completed, the mixture was controlled by 10% hydrochloricacid to show pH7 and further stirred for 24 hours. Crystals thus formedwere taken by filtration and washed with 5 mL of ethanol. Then the oilyproduct obtained by concentrating the washings was purified by silicagel column chromatography (chloroform:methanol=10:1 (V/V)) to obtain 321mg (0.71 mmol) of4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranosidein the form of white crystals.

¹H-NMR (300 MHz, DMSO-d6) δ: 2.43(3H, s), 3.15–3.25(4H, m), 4.39(1H, dd,J=5.3, 12.0 Hz), 3.67(1H, d, J=12.0), 3.75(2H, s), 4.92(1H, br-s),5.04(1H, br-s), 5.12(1H, br-s), 7.12(2H, d, J=8.7 Hz), 7.16(2H, d, J=8.7Hz). ESI-MS(m/z): 449[(M−H)⁻]

Example 2

Synthesis of4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-O-β-D-glucopyranosideuronic acid

Process 1

Synthesis of benzyl4′-[(4′-ethylphenyl)methyl]-5′-(trifluoromethyl)-1H-pyrazole-3′-yl-2,3,4-O-tribenzyl-β-D-glucopyranouronate

199 mg (0.359 mmol) of 2,3,4-tri-O-benzylβ-D-glucopyranoside uronic acidbenzyl ester (SIGMA), 99 mg (0.367 mmol) of1,2-dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazole-3-one(prepared by methods described in J. Med. Chem. 1996, 39, 3920–3928) and109 mg (0.416 mmol) of triphenylphosphane were dissolved in 0.5 ml ofdried THF (not containing stabilizer). 0.18 ml (0.40 mmol) of 40%toluene solution of diethyl azodicarboxylate was added thereto undercooling with ice and the mixture was stirred at room temperature for 1.5hours. The reaction mixture was directly purified by silica gelchromatography (hexane˜ethyl acetate:hexane=1:10˜1:5) and concentratedunder reduced pressure to obtain 127 mg (0.157 mmol) of benzyl4′-[(4′-ethylphenyl)methyl]-5′-(trifluoromethyl)-1H-pyrazole-3′-yl-2,3,4-O-tribenzyl-β-D-glucopyranouronatein the form of pale yellow oily product.

¹H-NMR (300 MHz, DMSO-d6) δ: 1.12 (3H, t, J=7.8 Hz), 2.50 (2H, q, J=7.8Hz), 3.64–3.86 (4H, m), 3.90–4.02 (1H, m), 4.05–4.20 (1H, m), 4.40–4.58(3H, m), 4.65–4.82 (3H, m), 5.10 (1H, d, J=12.1 Hz), 5.15(1H, d, J=12.1Hz), 5.20–5.30 (1H, br), 6.90–7.35 (24H, m)

Process 2

Synthesis of4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-O-β-D-glucopyranosideuronic acid

122 mg (0.151 mmol) of benzyl4′-[(4′-ethylphenyl)methyl]-5′-(trifluoromethyl)-1H-pyrazole-3′-yl-2,3,4,-O-tribenzyl-β-D-glucopyranouronatewas dissolved in 4 ml of ethyl acetate and 4 ml of methanol and, in thepresence of 204 mg of 20%-palladium hydroxide-carbon (50% wet, Aldrich)under hydrogen atmosphere at normal pressures, stirred at roomtemperature for 8 hours. After filtrating 20%-palladium hydroxide-carbonand washing the mixture with 100 ml of dichloromethane:methanol (4:1),the filtrate was evaporated under reduced pressure. The obtained solidsubstance was suspended in the distilled water and purified by SedPackcolumn (water:methanol=1:0˜0:1). Then the product was evaporated underreduce pressure at 40° C. in the bath or lower to obtain 22 mg (0.050mmol) of4-[(4-ethylphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid in the form of amorphous white solid substance.

¹H-NMR (300 MHz, DMSO-d6) δ: 1.19 (3H, t, J=7.5 Hz), 2.58 (2H, q, J=7.5Hz), 3.35–3.51 (2H, m), 3.52–3.65 (1H, m), 3.70–3.90 (3H, m), 5.00–5.20(1H, br), 7.06 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz) ESI-MS(m/z)445[(M−H)⁺], 447[(M+H)⁺]

Example 3

Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-β-D-glucopyranoside

Process 1

Synthesis of4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

4.76 g (17.6 mmol) of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3H-pyrazole-3-one(prepared by methods described in J. Med. Chem. 1996, 39, 3920–3928) and1.57 g (23.1 mmol) of imidazole were dissolved in 20 ml ofdimethylformamide. 2.98 g (19.8 mmol) of t-butyldimethylsilylchloridewas added thereto and the mixture was stirred at room temperature for 30minutes. After adding 100 ml of water, the mixture was extracted with amixed solution of ethyl acetate-hexane (2:1) three times. The organiclayer was washed with water, dried over sodium sulfate and concentratedto obtain 6.9 g of the intended product (17.9 mmol, quantitative).

¹H-NMR(300 MHz, CDCl₃) δ: 0.21 (6H, s), 0.93 (9H, s), 1.19 (3H, t, J=7.6Hz), 2.59 (2H, q, J=7.6 Hz), 3.74 (2H, s), 7.09 (4H, pseudo ABq)ESI-MS(m/z) 269 [(M−TBS)⁻]

Process 2

Synthesis of4-[(4-methylphenyl)methyl]-1-benzyl-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

0.39 g (1.0 mmol) of4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole,0.30 g (1.1 mmol) of triphenylphosphane and 0.14 ml (1.4 mmol) of benzylalcohol were dissolved in 2.0 ml of anhydrous tetrahydrofuran andstirred at room temperature. 0.50 ml (1.1 mmol) of 40% toluene solutionof diethyl azodicarboxylate was slowly added thereto and, 20 minuteslater, the mixture was concentrated. Then 1 ml of hexane was added, andformed sediments were taken by filtration, concentrated and purified bysilica gel column hexane→5% ethyl acetate/hexane) to obtain 0.40 g (0.83mmol) of the intended product (83%).

¹H-NMR(300 MHz, CDCl₃) δ: 0.22 (6H, s), 0.92 (9H, s), 1.20 (3H, t, J=7.5Hz), 2.59 (2H, q, J=7.5 Hz), 3.74 (2H, s), 5.19 (2H, s), 7.06 (4H,pseudo ABq), 7.11–7.33 (5H, m)

Process 3

Synthesis of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole

0.40 g (0.83 mmol) of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazolewas dissolved in 2 ml of tetrahydrofuran and 0.5 ml of methanol and 1 mlof 1M-HCl aqueous solution was added thereto and the mixture was stirredat room temperature for 7 hours. After adding 5 ml of water, the mixturewas extracted with 5 ml of ethyl acetate three times. The product wasdried over sodium sulfuric anhydride, concentrated and purified bysilica gel column (hexane→10% ethyl acetate/hexane) to obtain 0.27 g(0.74 mmol) of the intended product (89%).

¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.6 Hz), 2.61 (2H, q, J=7.6Hz), 3.77 (2H, s), 5.18 (2H, s), 7.07–7.31 (9H, m) ESI-MS(m/z) [361(M+H)⁺],[359 (M−H)⁻]

Process 4

Synthesis of4′-[(4-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

1 mL of water and 10 mL of chloroform were added to 0.22 g (0.62 mmol)of 4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole,0.39 g (0.94 mmol) of 2,3,4,6-O-tetraacetyl-α-D-glucopyranosyl bromide,0.055 g (0.18 mmol) of benzyl tri-n-butylammonium chloride, 0.79 g (5.7mmol) of potassium carbonate and the mixture was stirred at roomtemperature overnight. About 0.1 g of benzyl tri-n-butylammoniumchloride was added thereto and the mixture was further stirredovernight. The organic layer was purified by silica gel columnchromatography (ethyl acetate:hexane=10:1) to obtain 0.39 of roughlypurified substance containing the intended product mainly and thefurther reaction proceeded.

¹H-NMR(300 MHz, CDCl₃) δ: 1.19 (3H, t, J=7.6 Hz), 1.86 (3H, s), 2.015(3H, s), 2.019 (3H, s), 2.03 (3H, s), 2.58 (2H, q, J=7.6 Hz), 3.74 (2H,s), 3.81 (1 H; dd, J=9.5, 4.2, 2.3 Hz), 4.08 (1H, dd, J=12.5, 2.3 Hz),4.27 (1H, dd, J=12.5, 4.2 Hz), 5.16–5.28 (3H, m), 5.24 (2H, s),5.58–5.63 (1H, m), 7.05 (4H, s), 7.16–7.35 (5H, m) ESI-MS(m/z) [691(M+H)⁺]

Process 5

Synthesis of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

0.28 g of roughly purified substance of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidewas dissolved in 5 ml of ethanol and 5 ml of 4N NaOH aqueous solutionwas added thereto and the mixture was stirred at room temperature. 1hour later, 50 ml of water was added and the mixture was extracted withethyl acetate five times. Then the product was concentrated and purifiedby silica gel column (dichloromethane→10% methanol/dichloromethane) toobtain 0.11 g (0.21 mmol) of the intended product.

¹H-NMR(300 MHz, CD30D) δ: 1.19 (3H, t, J=7.6 Hz), 2.58 (2H, q, J=7.6Hz), 3.34–3.46 (4H, m), 3.68 (1H, dd, J=12.0, 4.7 Hz), 3.81 (1H, dd,J=12.0, 2.1 Hz), 3.83 (2H, s), 5.32 (2H, s), 5.34–5.37 (1H, m), 7.07(4H, s), 7.10–7.12 (2H, m), 7.25–7.33 (3H, m)

Example 4

Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

0.11 g (0.2 1 mmol) of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-β-D-glucopyranosidewas dissolved in 1.5 ml of pyridine and cooled in the ice bath. 0.020 ml(0.26 mmol) of methyl chlorocarbonate was added thereto and thetemperature of the mixture was raised up to room temperature in 0.5hour. 0.020 ml (0.26 mmol) of methyl chlorocarbonate was further added 2hours later and 19 hours later, then the mixture was stirred at roomtemperature for 6 hours. 5 ml of ethyl acetate, 10 ml of 1M HCl aqueoussolution and 20 ml of water were added thereto and the mixture wasextracted with ethyl acetate. Then the product was dried, concentratedand purified by silica gel column (ethyl acetate) to obtain 0.059 g(0.10 mmol) of the intended product (47%).

¹H-NMR(300 MHz, CDCl3) δ: 1.18 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6Hz), 3.48–3.60 (4H, m), 3.70 (3H, s), 3.74 (1H, d, J=15.8 Hz), 3.82 (1H,d, J=15.8 Hz), 4.34 (2H, s), 5.22 (1H, d, J=4.4 Hz), 5.23 (2H, s), 7.07(4H, s), 7.12 (2H, d, J=6.4 Hz), 7.21–7.32 (3H, m) ESI-MS(m/z) [581(M+H)³⁰ ], [579 (M−H)⁻]

Example 5

Synthesis of4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

Process 1

Synthesis of4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

The intended product was obtained in the same manner as shown in Process2 of Example 3, by using 4-methoxy benzyl bromide instead of benzylbromide.

¹H-NMR(300 MHz, CDCl₃) δ: 0.22 (6H, s), 0.93 (9H, s), 1.19 (3H, t, J=7.6Hz), 2.58 (2H, q, J=0.6 Hz), 3.72 (2H, s), 3.78 (3H, s), 5.14 (2H, s),6.83 (2H, d, J=8.8 Hz), 7.07 (4H, pseudo ABq), 7.16 (2H, d, J=8.8 Hz)

Process 2

Synthesis of4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazole

The intended product was obtained (82%) from4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3-O-t-butyldimethylsilyl-1H-pyrazolein the same manner as shown in Process 3 of Example 3

¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.5 Hz), 2.60 (2H, q, J=7.5Hz), 3.77 (5H, s), 5.10 (2H, s), 6.81–6.84 (2H, m), 7.07–7.19 (6H, m)ESI-MS(m/z) [391 (M+H)⁺], [389 (M−H)⁻]

Process 3

Synthesis of 4′-[(4′-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

The roughly purified product of the intended product was obtained from4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazolein the same manner as shown in Process 4 of Example 3.

¹H-NMR(300 MHz, CDCl₃) δ: 1.19 (3H, t, J=7.6 Hz), 1.86 (3H, s), 2.07(3H, s), 2.11 (6H, s), 2.58 (2H, q, J=7.6 Hz), 3.73 (2H, s), 3.75–3.84(1H, m), 4.24–4.30 (1H, m), 5.16 (2H, s), 5.19–5.28 (3H, m), 5.56–5.60(1H, m), 6.75 (2H, d, J=8.8 Hz), 7.05 (4H, s), 7.15 (2H, d, J=8.8 Hz)ESI-MS(m/z) [721 (M+H)⁺]

Process 4

Synthesis of4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

The intended product was obtained (91% in 2 steps) from4′-[(4′-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 3.

¹H-NMR(300 MHz, CD30D) δ: 1.19 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6Hz), 3.36–3.44 (4H, m), 3.66–3.82 (2H, m), 3.76 (3H, s), 3.82 (2H, s),5.24 (2H, s), 5.33–5.36 (1H, m), 6.86 (2H, d, J=8.5 Hz), 7.07 (4H, s),7.12 (2H, d, J=8.5 Hz) ESI-MS(m/z) [553 (M+H)⁺], [551 (M−H)⁻]

Example 6

Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-[(4′-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

0.18 g (0.32 mmol) of4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranosidewas dissolved in 2 ml of 2,4,6-collidine and cooled down to −50° C.0.035 ml(0.45 mmol) of methyl chlorocarbonate was added thereto and thetemperature of the mixture was raised up to room temperature in 1 hour.27 hours later, 20 ml of ethyl acetate and 20 ml of 1M HCl aqueoussolution were added thereto and the mixture was extracted with ethylacetate. Then the product was dried, concentrated and purified by silicagel column (hexane→ethyl acetate) to obtain 0.12 g (0.20 mmol) of theintended product (62%).

¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.6 Hz), 2.26 (1H, d, J=2.3Hz), 2.61 (2H, q, J=7.6 Hz), 2.69 (1H, s), 2.86 (1H, s), 3.45–3.61 (4H,m), 3.73 (1H, d, J=15.2 Hz), 3.80 (3H, s), 3.80 (3H, s), 3.88 (1H, d,J=15.2 Hz), 4.37 (1H, d, J=12.3 Hz), 4.49 (1H, dd, J=12.3, 3.0 Hz), 5.19(2H, s), 5.20 (1H, d, J=7.6 Hz), 6.86 (2H, d, J=8.5 Hz), 7.10 (4H, s),7.16 (2H, d, J=8.5 Hz)

Example 7

Synthesis, of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

Process 1

Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

0.079 g (0.21 mmol) of4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole,0.049 g (0.40 mmol) of phenylboronic acid and 0.057 g (0.32 mmol) ofcopper acetate anhydride were dissolved in 5 ml of drieddichloromethane. 0.15 g of molecular sieves 4A powder and 0.032 ml(0.40mmol) of pyridine were added thereto and the mixture was stirred at roomtemperature overnight. Then the reaction mixture was purified by silicagel column (hexane→hexane:dichloromethane=5:1˜3:1) and the main productwas separated to obtain 0.074 g (0.16 mmol) of the intended product(80%).

¹H-NMR(300 MHz, CDCl₃) δ: 0.27 (6H, s), 0.96 (9H, s), 1.21 (3H, t, J=7.6Hz), 2.61 (2H, q, J=7.6 Hz), 3.84 (2H, s), 7.11 (2H, J=8.3 Hz), 7.18(2H, J=8.3 Hz), 7.35–7.45 (5H, m) ESI-MS(m/z) [461 (M+H)⁺], [459 (M−H)⁻]

Process 2

Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole

The intended product was obtained (95%) from4-[(4-ethylphenyl)methyl]-1-phenyl-5-(trifluoromethyl)-3-O-t-butyldimethylsilyl-1H-pyrazolein the same manner as shown in Process 3 of Example 3.

¹H-NMR(300 MHz, CDCl) δ: 1.22 (3H, t, J=7.6 Hz), 2.62 (2H, q, J=7.6 Hz),3.81 (2H, s), 7.10 (2H, d, J=8.1 Hz), 7.17 (2H, d, J=8.1 Hz), 7.35–7.50(5H, m), 10.40–10.80 (1H, br-s) ESI-MS(m/z) [347 (M+H)⁺], [345 (M−H)⁻]

Process 3

Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

The roughly purified product of the intended product was obtained from4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole in thesame manner as shown in Process 4 of Example 3.

¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.6 Hz), 1.90 (3H, s), 2.02(3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.61 (2H, q, J=7.6 Hz), 3.80–3.90(2H, s and 1 H, m), 4.10–4.30 (2H, m), 5.15–5.36 (3H, m), 5.68 (1H, d,J=7.5 Hz), 7.10 (2H, d, J=8.3 Hz), 7.15 (2H, d, J=8.3 Hz), 7.38–7.47 (5H, m) ESI-MS(m/z) [677 (M+H)⁺]

Process 4

Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

The intended product was obtained (84% in 2 steps) from the roughlypurified product of4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 3.

¹H-NMR(300 MHz, DMSO-d₆) δ: 1.19 (3H, t, J=7.6 Hz), 2.60 (2H, q, J=7.6Hz), 3.15–3.35 (4H, m), 3.45–3.55 (1H, m), 3.69 (1H, dd, J=11.4, 5.7Hz), 3.85 (1H, d, J=15.6 Hz), 3.92 (1H, d, J=15.6 Hz), 4.55 (1H, t,J=5.7 Hz), 5.03 (1H, d, J=4.5 Hz), 5.13 (1H, d, J=3.9 Hz), 5.35 (1H, d,J=7.5 Hz), 5.41 (1H, d, J=4.5 Hz), 7.17 (2H, d, J=8.3 Hz), 7.22 (2H, d,J=8.3 Hz), 7.47–7.62 (5H, m) ESI-MS(m/z) [509 (M+H)⁺], [507 (M−H)⁻]

Example 8

Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

The intended product was obtained (71%) from4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranosidein the same manner as shown in Example 4.

¹H-NMR(300 MHz, CDCl₃) δ: 1.22 (3H, t, J=7.6 Hz), 2.18 (1H, br), 2.62(2H, q, J=7.6 Hz), 2.72 (1H, br), 2.89 (1H, br), 3.45–3.63 (4H, m), 3.78(3H, s), 3.81 (1H, d, J=15.6 Hz), 3.98 (1H, d, J=15.6 Hz), 4.37 (1H, dd,12.0, 1.7 Hz), 4.49 (1H, dd, 12.0, 3.6 Hz), 5.32 (1H, d, J=7.2 Hz), 7.14(2H, d, J=8.3 Hz), 7.19 (2H, d, J=8.3 Hz), 7.39–7.47 (5H, m) ESI-MS(m/z)[567 (M+H)⁺], [565 (M−H)⁻]

Example 9

Synthesis of4-[(3-fluoro-4-methoxylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

Process 1

Synthesis of ethyl 2-[(3-fluoro-4-methoxy)benzyl]-3-oxobutyrate

1.69 g (13.0 mmol) of ethyl acetoacetate and 9.6 g (65 mmol) of sodiumiodide were dissolved in 100 ml of acetonitrile and cooled down to 0C.8.2 ml(65 mmol) of trimethylsilylchloride was slowly added thereto and10 minutes later, 2.0 g (13.0 mmol) of 3-fluoro-4-methoxybenzaldehydewas added in three times. 10 minutes later, the temperature of themixture was raised up to room temperature and the mixture wascontinuously stirred. 6 hours later, the mixture was moved into the 60°C. bath and stirred overnight. After the reaction mixture was cooleddown, 250 ml of water, 250 ml of ethyl acetate and 50 ml of saturatedaqueous sodium chloride solution were added thereto, and ethyl acetatelayer was extracted. The obtained organic layer was washed withsaturated sodium sulfite aqueous solution and dried over anhydrousmagnesium sulfate. Then the product was concentrated and purified bysilica gel column chromatography (EtOAc-Hex; 1:4) to obtain 2.54 g (9.5mmol) of the intended product (yield 73%).

¹H-NMR (300 MHz, CDCl₃) δ: 6.82–6.96 (3H, m), 4.12–4.20 (2H, m), 3.86(3H, s) 3.71 (1H, t, J=7.8), 3.08 (2H, d, J=8.1), 2.20 (3H, s), 1.23(3H, t, J=7.2).

Process 2

Synthesis of1,2-dihydro-4-[(3-fluoro-methoxyphenyl)methyl]-5-methyl-3H-pyrazole-3-one

2.54 g (9.5 mmol) of elthyl2-[(3-fluoro-4-methyloxy)benzyl]-3-oxobutyrate was dissolved in 50 ml oftoluene. 0.72 g (14.2 mmol) of hydrated hydrazine was added thereto andthe mixture was stirred at 100° C. overnight. After the reaction mixturewas cooled down, the formed white solid was filtrated and dried by avacuum pump to obtain 1.86 g (7.9 mmol) of the intended product (yield83%).

¹H-NMR (300 MHz, DMSO-d6) δ: 7.00 (1H, t, J=8.4), 6.86–6.94 (2H, m),3.75 (3H, s), 3.46 (2H, s), 1.98 (3H, s). ESI-MS(m/z): 237[(M+H)⁺],235[(M−H)⁻].

Process 3

Synthesis of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

2.3 g (4.2 mmol) of 2,3,4,6-tetra-O-benzylβ-D-glucopyranoside, 1.0 g(4.2 mmol) of1,2-dihydro-4-[(3-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazole-3-oneand 1.1 g (4.2 mmol) of triphenylphosphane were dissolved in 40 ml ofdried THF (not containing stabilizer). 1.9 ml(4.2 mmol) of 40% toluenesolution of diethyl azodicarboxylate was added thereto under coolingwith ice and the mixture was stirred at room temperature overnight.After the reaction mixture was concentrated, the product was directlypurified by silica gel column chromatography (hexane˜ethylacetate:hexane=2:3) and concentrated under reduced pressure to obtain2.2 g (2.9 mmol) of the intended product (yield 70%).

¹H-NMR (300 MHz, CDCl₃) δ: 7.10–7.32 (20H, m), 6.78–6.92 (2H, m), 6.67(1H, t, J=8.1), 5.51 (1H, d, J=7.5), 4.46–4.92 (1OH, m), 3.60–3.76 (6H,m), 3.71 (3H, s), 2.07 (3H, s). ESI-MS(m/z): 759[(M+H)⁺], 757[(M−H)⁻].

Process 4

Synthesis of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl-β-D-glucopyranoside

2.2 g (2.9 mmol) of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidewas dissolved in 44 ml of dimethylformamide. 9.6 g (29.5 mmol) of cesiumcarbonate and 2.5 g (14.8 mmol) of isopropyl iodide were added theretoand the mixture was stirred at room temperature overnight.

200 ml of water, 50 ml of saturated aqueous sodium chloride solution and300 ml of dichloromethane were added and the organic layer wasextracted, dried over anhydrous sodium sulfate and concentrated. Theproduct was purified by silica gel column chromatography (hexane˜ethylacetate:hexane=1:3) and concentrated under reduced pressure to obtain1.7 g (2.2 mmol) of the intended product (yield 74%).

¹H-NMR (300 MHz, CDCl₃) δ: 7.12–7.32 (20H, m), 6.80–6.92 (2H, m), 6.68(1H, t, J=8.4), 5.47 (1H, d, J=7.2), 4.74–4.94 (5H, m), 4.44–4.64 (5H,m), 4.24–4.32 (1H, m), 3.73 (3H, s), 3.60–3.72 (6H, m), 2.06 (3H, s),1.38 (3H, t, J=7.5). ESI-MS(m/z): 801[(M+H)⁺].

Process 5

Synthesis of4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

1.7 g (2.2 mmol) of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidewas dissolved in 70 ml of ethanol. 1.0 g of 20% palladiumhydroxide—carbon was added thereto and the mixture was stirred for 2hours under hydrogen atmosphere. The reaction mixture was filtrated by afilter cell and the filtrate was concentrated and purified by silica gelchromatography (15% methanol: dichloromethane) and then concentratedunder reduced pressure to obtain 828 mg (1.9 mmol) of the intendedproduct (yield 88%).

¹H-NMR (300 MHz, DMSO-d6) δ: 6.92–7.04 (3H, m), 5.20 (1H, d, J=4.5),5.11 ( 1H, d, J=7.2), 5.02 (1H, d, J=3.6), 4.93 (1H, d, J=4.5), 4.41(1H, t, J=5.7), 4. 28–4.40 (1H, m), 3.77 (3H, s), 3.56–3.66 (1H, m),3.42–3.52 (1H, m), 3.08–3.24 (4H, m), 2.07 (3H, s), 1.24–1.30 (3H, m).ESI-MS(m/z): [441(M+H)⁺].

Example 10

Synthesis of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

820 mg (1.9 mmol) of4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranosidewas dissolved in 8 ml of collidine and cooled down to 0° C. 10 minuteslater, 0.22 ml of methyl chlorocarbonate was added thereto and themixture was stirred for 7 hours, neutralized with 2N HCl and extractedwith ethyl acetate. Then the organic layer was dried over anhydroussodium sulfate, concentrated and purified by silica gel chromatography(ethyl acetate) and then concentrated under reduced pressure to obtain303 mg (0.61 mmol) of the intended product (yield 33%).

¹H-NMR (300 MHz, CDCl₃) δ: 6.80–6.92 (3H, m), 5.02 (1H, d, J=8.1), 4.40(2H, s), 4.22–4.34 (1H, m), 3.85 (3H, s), 3.78 (3H, s), 3.44–3.66 (6H,m), 2.08 (3H, s), 1.38 (6H, d, J=6.6). ESI-MS(m/z): [499(M+H)⁺].

Example 11

Synthesis of4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3O-βD-glucopyranoside

Process 1

Synthesis of ethyl 2-[(2-fluoro-4-methoxy)benzyl]-3-oxobutyrate

3.4 g (12.7 mmol) of the intended product was obtained (yield 65%) from3.0 g of 2-fluoro-4-methoxybenzaldehyde in the same manner as shown inProcess 1 of Example 9.

¹H-NMR (300 MHz, CDCl₃) δ: 7.07 (1H, t, J=8.7), 6.40–6.62 (2H, m),4.10–4.20 (2H, m), 3.79 (1H, t, J=7.8), 3.77 (3H, s), 3.04–3.18 (2H, m),2.21 (3H, s), 1.21 (3H, t, J=7.2).

Process 2

Synthesis of1,2-dihydro-4-[(2-fluoro-4-methoxylphenyl)methyl]-5-methyl-3H-pyrazole-3-one

2.46 g (10.4 mmol) of the intended product was obtained (yield 83%) from3.4 g of ethyl 2-[(2-fluoro-4-methoxy)benzyl]-3-oxobutyrate in the samemanner as shown in Process 2 of Example 9.

¹H-NMR (300 MHz, CDCl₃) δ: 7.02 (1H, t, J=8.7), 6.72 (1H, dd, J=2.4,12.0), 6.66 (1H, d, J=2.7, 8.4), 3.71 (3H, s), 3.47 (2H, s), 1.99 (3H,s) ESI-MS(m/z) 237[(M+H)⁺], 235[(M−H)⁻].

Process 3

Synthesis of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

2.6 g (3.46 mmol) of the intended product was obtained (yield 82%) from1.0 g (4.2 mmol) of1,2-dihydro-4-[(2-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazole-3-onein the same manner as shown in Process 3 of Example 9.

¹H-NMR (300 MHz, DMSO-d6) δ: 7.12–7.32 (20H, m), 6.99 (1H, t, J=9.0),6.50 (1H, dd, J=2.4, 11.7), 6.42 (1H, dd, J=2.7, 8.4), 5.54 (1H, d,J=7.2), 4.44–4.92 (8H, m), 3.60–3.76 (8H, m), 3.62 (3H, s), 2.09 (3H, s)ESI-MS(m/z): 759[(M+H)⁺], 757[(M−H)⁻].

Process 4

Synthesis of4′-[(2′-fluoro-4′-methoxyphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

157 mg (0.19 mmol) of the intended product was obtained (yield 70%) from212 mg (0.28 mmol) of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidein the same manner as shown in Process 4 of Example 9.

¹H-NMR (300 MHz, CDCl₃) δ: 7.14–7.30 (20H, m), 6.99 (1H, t, J=8.7), 6.49(1H, dd, J=2.4, 11.7), 6.41 (1H, dd, J=2.4, 8.7), 5.50 (1H, d, J=7.5),4.74–4.96 (5H, m), 4.46–4.66 (5H, m), 4.22–4.32 (1H, m), 3.64 (3H, s),3.60–3.74 (6H, m), 2.08 (3H, s), 1.37 (6H, t, J=6.6). ESI-MS(m/z):801[(M+H)⁺].

Process 5

Synthesis of4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

80 mg (0.18 mmol) of the intended product was obtained (yield 97%) from150 mg (0.19 mmol) of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-Sβ-D-glucopyranoside in the same manner as shown in Process 5 of Example9.

¹H-NMR (300 MHz, DMSO-d6) δ: 7.09 (1H, t, J=9.0), 6.73 (1H, dd, J=2.7,12.3), 6.66 (1H, dd, J=2.7, 8.7), 5.18 (1H, d, J=4.8), 5.11 (1H, d,J=7.5), 5.01 (1H, d, J=4.2), 4.91 (1H, d, J=4.2), 4.42 (1H, t, J=6.0),4.30–4.38 (1H, m), 3.72 (3H, s) 3.53 (2H, s), 3.42–3.66 (2H, m),3.06–3.24 (4H, m), 2.07 (3H, s), 1.28 (3H, d, J=2.7), 1.26 (3H, d,J=2.7). ESI-MS(m/z): 441[(M+H)⁺], 4.39[(M−H)⁻].

Example 12

Synthesis of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

380 mg (0.76 mmol) of the intended product was obtained (yield 310%)from 1.1 g (2.42 mmol) of4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside.

¹H-NMR (300 MHz, CDCl₃) δ: 7.08 (1H, t, J=8.4), 6.52–6.62 (2H, m), 5.02(1H, d, J=7.8), 4.64 (1H, brs), 4.40 (2H, d, J=2.4), 4.24–4.33 (1H, m),3.77 (3H, s), 3.75 (3H, s), 3.59 (3H, s), 3.10–3.66 (6H, m), 1.38 (3H,s), 1.35 (3H, s)

Example 13

Synthesis of4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

Process 1

Synthesis of ethyl 2-[(3-fluoro-4-methyl)benzyl]-3-oxobutyrate

4.5 g (17.9 mmol) of the intended product was obtained (yield 82%) from3.0 g (21.7 mmol) of 3-fluoro-4-methlylbenzaldehyde in the same manneras shown in Process 1 of Example 9.

¹H-NMR (300 MHz, CDCl₃) δ: 7.06 (1H, t, J=8.1), 6.78–6.88 (2H, m), 4.15(2H, q, J=6.9), 3.73 (1H, t, J=7.8), 3.10 (1H, d, J=7.8), 2.22 (3H, s),2.19 (3H, s), 1.22 (3H, t, J=6.9).

Process 2

Synthesis of1,2-dihydro-4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3H-pyrazole-3one

2.3 g (10.5 mmol) of the intended product was obtained (yield 93%) from2.84 g (11.3 mmol) of ethyl 2-[(3-fluoro-4-methyl)benzyl]-3-oxobutyratein the same manner as shown in Process 2 of Example 9.

¹H-NMR (300 MHz, DMSO-d6) δ: 7.11 (1H, d, J=8.4), 6.81–6.89 (2H, m),3.49 (2H, s), 2.13 (3H, s), 1.98 (3H, s). ESI-MS(m/z): 221[(M+H)⁺]

Process 3

Synthesis of4′-[(3′-fluoro-4′-methylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

2.1 g (5.0 mmol) of 2,3,4,6-O-tetraacetyl-α-D-glucopyranosyl bromide,1.1 g (5.0 mmol) of1,2-dihydro-4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3H-pyrazole-3-oneand 1.38 g (5 mmol) of silver carbonate were dissolved in 50 ml of driedTHF (not containing stabilizer) and the mixture was stirred under darkat 65° C. overnight. The reaction mixture was filtrated with a filtercell and dichloromethane was added thereto. After washing the mixturewith water, the organic layer was dried over anhydrous sodium sulfate,concentrated and purified by silica gel chromatography (hexane˜ethylacetate:hexane=1:3) and then concentrated under reduced pressure toobtain 1.1 g (2.0 mmol) of the intended product (yield 40%).

¹H-NMR (300 MHz, CDCl₃) δ: 7.03 (1H, t, J=7.5), 6.82 (1H, dd, J=1.2,7.8), 6.74 (1H, dd, J=1.5, 10.8), 5.59 (1H, d, J=8.1), 5.16–5.30 (3H,m), 4.31 (1H, dd, J=3.9, 12.3), 4.12 (1H, dd, J=2.1, 12.3), 3.82–3.88(1H, m), 3.63 (1H, d, J=15.9), 3.54 (1H, d, J=15.9), 2.20 (3H, d,J=1.5), 2.11 (3H, s), 2.06 (3H, s), 2.03 (3H, s), 2.02 (3H, s), 1.91(3H, s). ESI-MS(m/z): 551[(M+H)⁺], 549[(M−H)⁻].

Process 4

Synthesis of4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-P)β-D-glucopyranoside

290 mg (0.53 mmol) of4′-[(3′-fluoro-4′-methylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidewas dissolved in 6 ml of dimethylformaldehyde. 1.7 g (5.2 mmol) ofcesium carbonate and 447 mg (2.6 mmol) of isopropyl iodide were addedthereto and the mixture was stirred at room temperature over night.After adding water, saturated aqueous sodium chloride solution anddichloromethane, the organic layer was extracted by a separating funnel,dried over anhydrous sodium sulfate and concentrated. The product waspurified by silica gel chromatography (hexane˜ethyl acetate:hexane=1:3)and then concentrated under reduced pressure to obtain 165 mg (0.28mmol) of the intended product (yield 53%).

¹H-NMR (300 MHz, CDCl₃) δ: 7.02 (1H, t, J=7.8), 6.82 (1H, d, J=7.8),6.74 (1H, d, J=10.8), 5.79 (1H, d, J=8.1), 5.12–5.34 (3H, m), 4.18–4.32(2H, m), 4.06–4.16 (1H, m), 3.78–3.88 (1H, m), 3.48–3.64 (2H, m), 2.19(3H, s), 2.07 (3H, s), 2.06 (3H, s), 2.04 (3H, s), 2.02 (3H, s), 1.93(3H, s). ESI-MS(m/z): 593[M⁺].

Process 5

Synthesis of4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

56 mg (0.09 mmol) of4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside was dissolved in 0.2 ml ofmethanol and 0.4 ml of tetrahydrofuran. 0.38 ml of 1N LiOH was added at0° C. thereto and the mixture was stirred for 1 hour. After adding waterand ethyl acetate, the organic layer was extracted, dried, concentratedand purified by silica gel chromatography (15% methanol:dichloromethane) and then concentrated under reduced pressure to obtain34 mg (0.08 mmol) of the intended product (yield 85%).

¹H-NMR (300 MHz, DMSO-d6) δ: 7.11 (1H, t, J=8.4), 5.19 (1H, d, J=4.8),5.09 (1H, d, J=7.5), 4.99 (1H, d, J=3.9), 4.91 (1H, d, J=4.2), 4.41 (1H,t, J=5.7), 4.28–4.38 (1H, m), 3.56 (2H, m), 3.54–3.64 (1H, m), 3.40–3.50(1H, m), 3.06–3.24 (4H, m), 2.13 (3H, s), 2.05 (3H, s), 1.26 (3H, d,J=3.0), 1.24 (3H, d, J=3.0). ESI-MS(m/z): 425[(M+H)⁺], 423[(M−H)⁻].

Example 14

Synthesis of4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

283 mg (0.59 mmol) of the intended product was obtained (yield 75%) from334 mg (0.787 mmol) of4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranosidein the same manner as shown in Example 12.

¹H-NMR (300 MHz, DMSO-d6) δ: 1.26(3H, d, J=6.3 Hz), 1.28(3H, d, J=6.3Hz), 2.07(3H, s), 2.15(3H, s), 3.09–3.41(4H, m), 3.56(2H, s), 4.10(1H,dd, J=6.0, 11.4 Hz), 4.29(1H, dd, J=1.8, 11.7 Hz), 4.34(1H, m), 5.10(1H,d, J=7.8 Hz), 5.13(1H, d, J=5.1 Hz), 5.24(1H, d, J=5.1 Hz), 5.31(1H, d,J=5.1 Hz), 6.89–7.13(3H, m). ESI-MS(m/z): 483[M+H]⁺ 481[(M−H)⁻]

Example 15

Synthesis of4-[(4-ethylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

Process 1

Synthesis of ethyl 2-(4-ethylbenzyl)-3-oxobutylate

3.9 g (]5.7 mmol) of the intended product was obtained (yield 70%) from3.0 g of 4-ethylbenzaldehyde in the same manner as shown in Process 1 ofExample 9.

¹H-NMR (300 MHz, CDCl₃) δ: 4.15 (2H, q, J=7.2), 3.76 (1H, t, J=7.5),3.12 (2H, d, J=8.1), 2.60 (2H, q, J=7.8), 2.19 (3H, s), 1.21 (6H, t,J=7.2)

Process 2

Synthesis of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-methyl-3H-pyrazole-3-one

3.1 g (14.3 mmol) of the intended product was obtained (yield 91%) from3.9 g of ethyl 2-(4-ethylbenzyl)-3-oxobutyrate in the same manner asshown in Process 2 of Example 9.

¹H-NMR (300 MHz, DMSO-d6) δ: 7.06 (4H, s), 3.49 (2H, s), 2.52 (2H, q,J=7.8), 1.99 (3H, s), 1.33 (3H, t, J=7.5) ESI-MS(m/z): 217[(M+H)⁺],215[(M−H)⁻].

Process 3

Synthesis of4′-[(4-ethylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

2.3 g (3.1 mmol) of the intended product was obtained (yield 62%) from1.0 g (4.6 mmol) of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-methyl-3H-pyrazole-3-one in thesame manner as shown in Process 3 of Example 9.

¹H-NMR (300 MHz, CDCl₃) δ: 7.10–7.34 (20H, m), 7.07 (2H, d, J=8.4), 6.97(2H, d, J=8.4), 5.23 (1H, d, J=6.9), 4.44–5.00 (8H, m), 3.56–3.80 (8H,m), 2.50 (2H, q, J=7.5), 2.08 (3H, s), 1.13 (3H, t, J=7.5): ESI-MS(m/z):739[(M+H)⁺], 737[(M−H)⁻].

Process 4

Synthesis of4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

1.6 g (2.0 mmol) of the intended product was obtained (yield 79%) from1.9 g (2.6 mmol) of4′-[(4-ethylphenyl)methyl]-5′-methyl-1H-pyryazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucolpyralosidein the same manner as shown in Process 4 of Example 9.

¹H-NMR (300 MHz, CDCl₃) δ: 7.14–7.38 (20H, m), 7.07 (2H, d, J=8.1), 6.97(2H, d, J=8.1), 5.47 (1H, d, J=7.5), 4.20–5.00 (9H, m), 3.60–3.76 (8H,m), 2.52 (2H, q J=7.8), 2.07 (3H, s), 1.37 (6H, t, J=6.9), 1.14 (3H, t,J=8.1): 781[(M+H)⁺].

Process 5

Synthesis of4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

743 mg (1.8 mmol) of the intended product was obtained (yield 87%) from1.6 g (2.0 mmol) of4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 9.

¹H-NMR (300 MHz, DMSO-d6) δ: 7.09 (2H, d, J-7.8), 7.03 (2H, d, J=7.8),5.18 (1H, brd, J=4.5), 5.11 (1H, d, J=6.9), 4.84–5.02 (2H, m), 4.26–4.44(3H, m), 3.40–3.64 (3H, m), 3.04–3.26 (4H, m), 2.51 (2H, q, J=7.5), 2.06(3H, s), 1.25 (6H, d, J=6.6), 1.14 (3H, t, J=5.7): 421[(M+H)⁺],419[(M−H)⁻].

Example 16

Synthesis of4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

570 mg (1.2 mmol) of the intended product was obtained (yield 71%) from702 mg (1.67 mmol) of4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranosidein the same manner as shown in Example 10.

¹H-NMR (300 MHz, CDCl₃) δ: 7.08 (4H, s), 4.99 (1H, d, J=7.5), 4.24–4.48(4H, m), 3.77 (3H, s), 3.44–3.68 (6H, m), 2.94–3.16 (2H, m), 2.58 (2H,q, J=7.8), 2.09 (3H, s), 1.36 (6H, d, J=6.6), 1.20 (3H, t, J=7.8)ESI-MS(m/z): 479[(M+H)⁺], 477[(M−H)⁻].

Referential Example 1 (Example 35 of WO01/16147)

Synthesis of4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

The product was synthesized in accordance with the methods described inExample 9 (yield point 253 mg).

¹H-NMR (300 MHz, DMSO-d6) δ: 7.07 (1H, d, J=8.4), 6.75 (1H, d, J=8.4),5.12–5.20 (2H, m), 5.00 (1H, d, J=3.9), 4.92 (1H, d, J=3.9), 4.42–4.56(2H, m), 3.58–3.68 (1H, m), 3.51 (2H, s), 3.42–3.54 (1H, m), 3.06–3.24(4H, m), 2.00 (3H, s), 1.22 (6H, d, J=6.3) ESI-MS(m/z): 409[(M+H)⁺],407[(M−H)⁻].

The structures of the compounds shown in Example 1 to 16 and ReferentialExample 1 are described as follows:

Example 17

Evaluation of Inhibiting Activity on Renal Brush Border Membrane GlucoseUptake

The test compound was dissolved in 100 mM Mannitol-10 mM HEPES/Tris(pH7.4) and solutions having various concentrations were prepared. Renalbrush border membrane was prepared from a rat kidney and the solutionsof the test compounds were added thereto and the product was incubatedat 37° C. for 30 minutes. Then ¹⁴C-D-glucose was added and the mixturewas incubated for 1 minute. After the reaction of glucose uptake wasstopped by a solution containing 1 mM of phloridzin, the activity of¹⁴C-D-glucose on ¹⁴C was measured by a liquid scintillation counter. Theintensity of inhibition was calculated by subtracting the amount oftaken glucose that is independent on sodium from the amount of takenglucose of the object samples. The results of the evaluation are shownin Table 1.

TABLE 1 Inhibition intensity (concentration The test compounds of thetest compounds) Example Compound 1 84% (10 μM)  Example Compound 2 30%(100 μM)

Example 18

Evaluation of Activity on Rat's Sugar Urine Excretion

5-week old male Wistar rats (purchased from Charles River Japan, Inc.)were used in the experiment after they were housed in a metabolic cagefor about one week in advance. The test compounds were suspended inolive oil and 20 mg/ml solution was prepared so that the dosage givenper 1 kg of the weight of the rats was 5 ml.

After the rats were not fed for 4 hours, the test compounds were orallyadministered to them at 11 a.m. Their urine was collected, from thattaken just after the administration to that taken 24 hours after theadministration and its volume was measured. Then, the concentration ofglucose in urine was measured by glucose oxidase method and urinaryglucose excreted per a day and an individual was calculated. The resultsare shown in Table 2.

TABLE 2 The amount of excreted The dosage glucose in urine (mg) ExampleCompound 4 100 mg/kg 27 Example Compound 6 100 mg/kg 59 Example Compound8 100 mg/kg 4.1 Example Compound 10 100 mg/kg 734 Example Compound 14100 mg/kg 918 Example Compound 16 100 mg/kg 598  30 mg/kg 294  10 mg/kg263  3 mg/kg 28 Referential Example 100 mg/kg 14 Compound ]

It is obvious from the results shown above that the new pyrazolederivatives have higher inhibiting activity on glucose uptake andactivity on urinary glucose excretion.

Especially, the inventors have found that the compounds wherein thesubstituents of hydroxyl group of glucopyranosyl group are loweralkoxycarbonyl group such as methoxy carbonyl group act as, so-called, aprodrug and the compounds in the present invention have high activity onurinary glucose excretion when they are orally administered.

The inventors also have found that the compounds wherein any one of R1,R2, R4, or R5 of general formula (1A) has a fluorine atom haveparticularly high activity on urinary glucose excretion. It is obviousfrom Example 10 and Example 14.

Further, they have found that the compound of Example 16 hasparticularly high activity on urinary glucose excretion. Examplecompound 16, which has high, activity on urinary glucose excretion,still has high activity when the compound is orally administered inlower doses such as 30 mg/kg or lower. The intended compound is notspecifically described in WO01/16147.

Besides, Table 2 shows that the compounds of the present invention suchas example compounds 10, 14 and 16 have much higher activity on urinaryglucose excretion, as compared to Example 35 of WO01/16147 (ReferentialExample 1 of the present specification).

Namely, new pyrazole derivatives of the present invention showoutstanding antidiabetic activity and, therefore, they are highly usefulin the pharmaceutical industry.

1. A pyrazole compound of formula (1A) or (1B) or a pharmaceuticallyacceptable salt thereof:

wherein X represents a β-D-glucopyranosyl group, of which one or morehydroxyl groups may be acylated, or a β-D-glucuronyl group, of which oneor more hydroxyl groups may be acylated and a carboxyl group may beesterified; Y represents a lower alkyl group or a perfluoro lower alkylgroup; Z represents a hydrogen atom, a lower alkyl group, a perfluorolower alkyl group, an aralkyl group or a phenyl group; R1, R2, R4, andR5 may be the same or different and each represents a hydrogen atom, alower alkyl group, a perfluoro lower alkyl group, a lower alkoxy group,a perfluoro lower alkoxy group, a lower alkylthio group, a perfluorolower alkylthio group, a lower alkyl amino group, a halogeno group, alower alkanoyl group, a lower alkenyl group or a lower alkynyl group;and n represents an integer from 0 to 3, wherein at least one of R1, R2,R4, and R5 represents a lower alkyl group, a perfluoro lower alkylgroup, a lower alkoxy group, a perfluoro lower alkoxy group, a loweralkylthio group, a perfluoro lower alkylthio group, a lower alkyl aminogroup, a halogeno group, a lower alkanoyl group, a lower alkenyl groupor a lower alkynyl group; and R3 represents a lower alkyl group, aperfluoro lower alkyl group, a lower alkoxy group, a perfluoro loweralkoxy group, a lower alkylthio group, a perfluoro lower alkylthiogroup, a lower alkyl amino group, a halogeno group, a lower alkanoylgroup, a lower alkenyl group or a lower alkynyl group.
 2. The pyrazolecompound or pharmaceutically acceptable salt thereof of claim 1, whereinY in formula (1A) or (1B) represents a trifluoromethyl group.
 3. Thepyrazole compound or pharmaceutically acceptable salt thereof of claim1, wherein, in formula (1A) or (1B), Y represents a trifluoromethylgroup and n is
 1. 4. The pyrazole compound or pharmaceuticallyacceptable salt thereof of claim 1, wherein, in formula (1A) or (1B), Yrepresents a trifluoromethyl group, n is 1 and X represents aβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with a group selected from the group consisting of an alkanoylgroup having 2 to 20 carbon atoms, a lower alkoxycarbonyl group and abenzoyl group.
 5. The pyrazole compound or pharmaceutically acceptablesalt thereof of claim 1, wherein, in formula (1A) or (1B), Y representsa trifluoromethyl group, n is 1 and X is a β-D-glucuronyl group, ofwhich one or more hydroxyl groups may be acylated with a group selectedfrom the group consisting of an alkanoyl group having 2 to 20 carbonatoms, a lower alkoxycarbonyl group and a benzoyl group and its carboxylgroup may be esterified with a lower alkyl group.
 6. The pyrazolecompound or pharmaceutically acceptable salt thereof of claim 1,wherein, in formula (1A) or (1B), X represents a β-D-glucopyranosylgroup, of which one or more hydroxyl groups are acylated with a groupselected from the group consisting of an alkanoyl group having 2 to 20carbon atoms, a lower alkoxycarbonyl group and a benzoyl group.
 7. Thepyrazole compound or pharmaceutically acceptable salt thereof of claim1, wherein, in formula (1A) or (1B), X represents a β-D-glucopyranosylgroup, of which one or more hydroxyl groups are acylated with a loweralkoxycarbonyl group.
 8. The pyrazole compound or pharmaceuticallyacceptable salt thereof of claim 1, wherein, in formula (1A) or (1B), Yrepresents a lower alkyl group having 1 to 3 carbon atoms or a perfluorolower alkyl group having 1 to 6 carbon atoms; n is 1; X represents aβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with a group selected from the group consisting of an alkanoylgroup having 2 to 20 carbon atoms, a lower alkoxycarbonyl group and abenzoyl group; Z represents a hydrogen atom, a lower alkyl group having1 to 3 carbon atoms, an unsubstituted aralkyl group or an aralkyl groupof which an aryl part at the 4th position is a substituted orunsubstituted phenyl group; one of R1, R2, R4 and R5 is a halogenogroup, and R3 is a lower alkyl group having 1 to 4 carbon atoms, a loweralkoxy group having 1 to 4 carbon atoms, a lower alkenyl group having 1to 4 carbon atoms, or a lower alkynyl group having 1 to 4 carbon atoms.9. The pyrazole compound or pharmaceutically acceptable salt thereof ofclaim 1, wherein, in formula (1A) or (1B), Y represents a methyl group;n is 1; X represents a β-D-glucopyranosyl group, of which one or morehydroxyl groups may be acylated with a group selected from the groupconsisting of an alkanoyl group having 2 to 20 carbon atoms, a loweralkoxycarbonyl group and a benzoyl group; Z represents an isopropylgroup; R3 is a lower alkyl group having 1 to 4 carbon atoms; and R4 orR5 is a fluorine atom.
 10. The pyrazole compound or pharmaceuticallyacceptable salt thereof of claim 1, wherein, in formula (1A) or (1B), Yrepresents a methyl group; n is 1; X represents a β-D-glucopyranosylgroup, of which one or more hydroxyl groups may be acylated with a groupselected from the group consisting of an alkanoyl group having 2 to 20carbon atoms, a lower alkoxycarbonyl group and a benzoyl group; Zrepresents an isopropyl group; R3 is a lower alkoxy group having 1 to 4carbon atoms, and R4 or R5 is a fluorine atom.
 11. The pyrazole compoundor pharmaceutically acceptable salt thereof of claim 1, wherein, informula (1A) or (1B), Y represents a methyl group; n is 1; X representsa β-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with a group selected from the group consisting of an alkanoylgroup having 2 to 20 carbon atoms, a lower alkoxycarbonyl group and abenzoyl group; Z represents an isopropyl group, and R3 is a loweralkynyl group having 1 to 4 carbon atoms.
 12. The pyrazole compound orpharmaceutically acceptable salt thereof of claim 1, wherein, in formula(1A) or (1B), Y represents a methyl group; n is 1; X represents aβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with a group selected from the group consisting of an alkanoylgroup having 2 to 20 carbon atoms, a lower alkoxycarbonyl group and abenzoyl group; Z represents an isopropyl group; R3 is a lower alkynylgroup having 1 to 4 carbon atoms; and R4 or R5 is a fluorine atom. 13.The pyrazole compound or pharmaceutically acceptable salt thereof ofclaim 1, wherein, in formula (1A) or (1B), Y represents a methyl group;n is 1; X represents a β-D-glucopyranosyl group, of which one or morehydroxyl groups may be acylated with a group selected from the groupconsisting of an alkanoyl group having 2 to 20 carbon atoms, a loweralkoxycarbonyl group and a benzoyl group; Z represents an isopropylgroup; and R3 is a lower alkenyl group having 1 to 4 carbon atoms. 14.The pyrazole compound or pharmaceutically acceptable salt thereof ofclaim 1, wherein, in formula (1A) or (1B), Y represents a methyl group;n is 1; X represents a β-D-glucopyranosyl group, of which one or morehydroxyl groups may be acylated with a group selected from the groupconsisting of an alkanoyl group having 2 to 20 carbon atoms, a loweralkoxycarbonyl group and a benzoyl group; Z represents an isopropylgroup; R3 is a lower alkenyl group having 1 to 4 carbon atoms; and R4 orR5 is a fluorine atom.
 15. A pharmaceutical composition comprising apyrazole compound or pharmaceutically acceptable salt thereof ofclaim
 1. 16. A method for treating diabetes which comprisesadministering an effective amount of a pyrazole compound of claim 1 or apharmaceutically acceptable salt thereof to a patient in need thereof.17. A method for reducing renal glucose reabsorption, which comprisesadministering an effective amount of a pyrazole compound of claim 1 or apharmaceutically acceptable salt thereof, to a patient in need thereof.18. The pyrazole compound or pharmaceutically acceptable salt thereof ofclaim 1, wherein R1 and R2 each represents a hydrogen atom.
 19. Thepyrazole compound or pharmaceutically acceptable salt thereof of claim1, wherein one of R1, R2, R4 and R5 is halogeno group; and R3 is a loweralkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to4 carbon atoms, a lower alkenyl group having 1 to 4 carbon atoms, or alower alkynyl group having 1 to 4 carbon atoms.
 20. The pharmaceuticalcomposition of claim 15, wherein R1 and R2 each represents a hydrogenatom.
 21. The pharmaceutical composition of claim 15, wherein one of R1,R2, R4 and R5 is halogeno group; and R3 is a lower alkyl group having 1to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, alower alkenyl group having 1 to 4 carbon atoms, or a lower alkynyl grouphaving 1 to 4 carbon atoms.
 22. The method of claim 16, wherein R1 andR2 each represents a hydrogen atom.
 23. The method of claim 16, whereinone of R1, R2, R4 and R5 is halogeno group; and R3 is a lower alkylgroup having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4carbon atoms, a lower alkenyl group having 1 to 4 carbon atoms, or alower alkynyl group having 1 to 4 carbon atoms.
 24. The method of claim17, wherein R1 and R2 each represents a hydrogen atom.
 25. The method ofclaim 17, wherein one of R1, R2, R4 and R5 is halogeno group; and R3 isa lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy grouphaving 1 to 4 carbon atoms, a lower alkenyl group having 1 to 4 carbonatoms, or a lower alkynyl group having 1 to 4 carbon atoms.